Crystalline form of Eluxadoline

ABSTRACT

The present invention provides a novel crystalline form of Eluxadoline, Eluxadoline Form APO-I, a co-crystal of Eluxadoline and methyl nicotinate, compositions and processes for the preparation thereof, and the use of this crystalline form in the treatment of opioid-modulated disorders, and in particular, gastrointestinal disorders, including irritable bowel syndrome with diarrhea (IBS-D).

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 62/562,654, filed Sep. 25, 2017, the disclosure of whichis hereby incorporated in its entirety by reference.

TECHNICAL FIELD

The present invention is directed to a novel crystalline form ofEluxadoline, pharmaceutical compositions containing this form, processesfor its preparation, and its use in the treatment of opioid-modulateddisorders, including irritable bowel syndrome.

BACKGROUND

The compound5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propionyl]-[(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino}-methyl)-2-methoxybenzoicacid, commonly known as Eluxadoline, is described in WO 2003/092688 A2.Eluxadoline is an opioid receptor modulator, and is marketed in theUnited States as VIBERZI® for the treatment of irritable bowel syndromewith diarrhea (IBS-D).

Crystalline forms of Eluxadoline, including hydrated and solvated forms,are reported, for example, in WO 2009/009480 A2, WO 2017/015606 A1 andWO 2017/114446 A1. However, these reported crystalline forms areassociated with various problems, such as hygroscopicity, tendency todesolvation/dehydration during drying procedures or upon exposure to lowhumidity conditions; poor characterization leading to questions ofcontrollability and reproducibility, the incorporation or use ofsolvents classified as toxic according to established ICH (InternationalCouncil for Harmonisation of Technical Requirements for Pharmaceuticalsfor Human Use) guidelines such as Q3C(R6), or preparations that areimpractical for commercial use. The tendency of forms todesolvate/dehydrate limits their usefulness in commercial products sinceit requires specialised practices to avoid desolvation/dehydrationduring drying, handling, storage and formulation activities.Furthermore, the variable and/or undefined nature of some of these formshas regulatory implications, as the characteristics of an activepharmaceutical ingredient must be well-defined and controlled.

Different crystalline forms of the same compound may have differentpacking, thermodynamic, spectroscopic, kinetic, surface and mechanicalproperties. For example, different crystalline forms may have differentstability properties. A particular crystalline form may be moresensitive to heat, relative humidity (RH) and/or light. Alternatively oradditionally, a particular crystalline form may provide morecompressibility and/or density properties thereby providing moredesirable characteristics for formulation and/or product manufacturing.Particular crystalline forms may also have different dissolution rates,thereby providing different pharmacokinetic parameters, which allow forspecific forms to be used in order to achieve specific pharmacokinetictargets. Additionally, the particular solubility characteristics of agiven crystalline form in relation to undesired impurities can result indifferences in the chemical purity of different crystalline forms uponisolation. Differences in stability may result from changes in chemicalreactivity, such as differential oxidation. Such properties may providefor more suitable product qualities, such as a dosage form that is moreresistant to discolouration when comprised of a specific crystallineform. Different physical properties of crystalline forms may also affecttheir processing. For example, a particular crystalline form may be moreresistant to flow, or may be more difficult to filter and/or wash.

Although general approaches to crystalline form screening of activepharmaceutical ingredients are known, it is well established that theprediction of how a given compound will crystallize is not possible.Furthermore, prediction of the properties of any unknown crystallineforms, and how they will differ from other crystalline forms of the samecompound, remains even more elusive (Joel Bernstein, Polymorphism inMolecular Crystals, Oxford University Press, New York, 2002, page 9).

Therefore, there exists a need for novel crystalline forms ofEluxadoline for use in providing improved drug products containingEluxadoline and their manufacture.

SUMMARY OF THE INVENTION

The Eluxadoline crystalline form of the present invention exhibitsdifferences in properties when compared to the known crystalline formsof Eluxadoline. Properties that differ between the invention and knowncrystalline forms of Eluxadoline include the following: packingproperties such as molar volume, density and hygroscopicity;thermodynamic properties such as melting and solubility; kineticproperties such as dissolution rate and chemical/polymorphic stability;surface properties such as crystal habit; and/or mechanical propertiessuch as hardness, tensile strength, compactibility, tableting, handling,flow, and blending.

Differences in the properties of the crystalline form of the presentinvention provide practical advantages that can be exploited to meetspecific needs in the manufacture and formulation of Eluxadoline. Forexample, the crystalline form of the present invention resists polymorphconversion following storage at 40° C./75% R.H. (relative humidity) forat least 10 days. Additionally, the Eluxadoline crystalline form of thepresent invention does not incorporate volatile components, such asalcohol solvents. These properties are of benefit during the drying,handling and storage of both the drug substance and drug product,wherein exposure to ambient conditions is possible, and whereincrystalline forms that are subject to moisture uptake or solventdisplacement can be susceptible to polymorphic conversion ordegradation. Furthermore, the process for manufacturing of theEluxadoline crystalline form of the present invention that has beendeveloped uses solvents established by the ICH Q3C(R6) guideline asbeing of low toxic potential (“Class 3”), which is preferable forproduction of pharmaceutical agents when compared to solvents in Classes1 (Solvents to Be Avoided) or 2 (Solvents to Be Limited).

In addition, methyl nicotinate is included in the U.S. Food & DrugAdministration's (FDA's) Everything Added to Food in the United States(EAFUS) list, which contains ingredients added directly to food that theFDA has either approved as food additives, or has listed or affirmed asbeing GRAS (Generally Recognized as Safe). The GRAS list is an inventoryof substances generally recognized by the FDA as having been adequatelyshown to be safe under the conditions of intended use.

Accordingly, in a first aspect of the present invention, there isprovided a crystalline form of Eluxadoline that is a co-crystal ofEluxadoline and methyl nicotinate. Preferably, in the co-crystal of thefirst aspect, the molar ratio of Eluxadoline to methyl nicotinate in theco-crystal is between approximately 1:0.5 and 1:1.5. More preferably,the molar ratio of Eluxadoline to methyl nicotinate in the co-crystal isapproximately 1:1.

In a second aspect of the present invention, there is provided acrystalline form of Eluxadoline, APO-I, that is a co-crystal ofEluxadoline and methyl nicotinate characterized by a powder X-raydiffraction (PXRD) diffractogram comprising peaks, expressed in degrees2θ (±0.2°), at 6.4°, 6.9° and 11.4°. In a preferred embodiment of thesecond aspect, the PXRD diffractogram further comprises at least threepeaks, expressed in degrees 2θ (±0.2°), selected from the groupconsisting of: 8.7°, 9.9°, 12.7°, 14.8°, 15.8°, 17.5°, 18.9°, 19.8° and23.8°. In a further preferred embodiment of the second aspect, the PXRDdiffractogram further comprises peaks, expressed in degrees 2θ (±0.2°),at 8.7°, 9.9°, 12.7°, 14.8°, 15.8°, 17.5°, 18.9°, 19.8° and 23.8°.Preferably, the crystalline form of the second aspect of the inventionprovides a PXRD diffractogram that is substantially the same inappearance as the representative PXRD diffractogram of Eluxadoline FormAPO-I provided in FIG. 1. In this second aspect of the invention, themolar ratio of Eluxadoline to methyl nicotinate is preferablyapproximately 1:1.

In a third aspect of the present invention, there is provided apharmaceutical composition comprising a crystalline form of Eluxadolineaccording to the first or second aspects of the invention, and one ormore pharmaceutically acceptable excipients. Preferably, thepharmaceutical composition is in the form of a solid dosage form. Mostpreferably, the pharmaceutical composition is a tablet.

In a fourth aspect of the present invention, there is provided a use ofa crystalline form of Eluxadoline according to the first or secondaspects of the invention, or the pharmaceutical compositions of thethird aspect of the invention, in the treatment of opioid-modulateddisorders. In a preferred embodiment of the fourth aspect, theopioid-modulated disorder is pain or a gastrointestinal disorder. In afurther preferred embodiment of the fourth aspect, the gastrointestinaldisorder is selected from the group consisting of ulcerative colitis,Crohn's disease, irritable bowel syndrome with diarrhea (IBS-D) andalternating irritable bowel syndrome. Most preferably, thegastrointestinal disorder is irritable bowel syndrome with diarrhea(IBS-D).

In a fifth aspect of the present invention, there is provided a processfor preparing a crystalline form of Eluxadoline according to the firstor second aspects of the invention, comprising combining methylnicotinate and Eluxadoline in a solvent, and maintaining the mixture ata suitable temperature. In a preferred embodiment of the fifth aspect,the solvent is a C1-C3 alcohol selected from the group consisting ofmethanol, ethanol, n-propanol and 2-propanol. Preferably, the C1-C3alcohol is 2-propanol. In a further preferred embodiment of the fifthaspect, the suitable temperature is between approximately roomtemperature and approximately 80° C., more preferably the suitabletemperature is approximately 60° C. In another preferred embodiment ofthe fifth aspect, the Eluxadoline and methyl nicotinate are combined ina molar ratio of Eluxadoline:methyl nicotinate of between approximately1:25 and approximately 1:60. Most preferably, the Eluxadoline and methylnicotinate are combined in a molar ratio of between approximately 1:35and approximately 1:55.

Other aspects and features of the present invention will become apparentto those ordinarily skilled in the art upon review of the followingdescription of specific embodiments of the invention in conjunction withthe accompanying figures.

BRIEF DESCRIPTION OF THE DRAWING

Embodiments of the present invention are described, by way of exampleonly, with reference to the attached FIGURE.

FIG. 1 is a representative PXRD diffractogram of Eluxadoline Form APO-Ias prepared in Example 1.

DETAILED DESCRIPTION

The Eluxadoline crystalline form of the present invention exhibitsdifferences in properties when compared to the known crystalline formsof Eluxadoline. Properties that differ between the invention and knowncrystalline forms of Eluxadoline include the following: packingproperties such as molar volume, density and hygroscopicity;thermodynamic properties such as melting and solubility; kineticproperties such as dissolution rate and chemical/polymorphic stability;surface properties such as crystal habit; and/or mechanical propertiessuch as hardness, tensile strength, compactibility, tableting, handling,flow, and blending.

These differences in the properties of the crystalline form of thepresent invention provide practical advantages that can be exploited tomeet specific needs in the manufacture and formulation of Eluxadoline.For example, the crystalline form of the present invention resistspolymorph conversion following storage at 40° C./75% R.H. for at least10 days. Additionally, the Eluxadoline crystalline form of the presentdoes not incorporate volatile components, such as alcohol solvents.These properties are of benefit during the drying, handling and storageof both the drug substance and drug product, wherein exposure to ambientconditions is possible, and wherein crystalline forms that are subjectto moisture uptake or solvent displacement can be susceptible topolymorphic conversion or degradation. Furthermore, the processesdeveloped for the manufacture of the Eluxadoline crystalline form of thepresent invention use solvents established by ICH Q3C (R6) guideline asbeing of low toxic potential (“Class 3”), which is preferable forproduction of pharmaceutical agents in Classes 1 (Solvents to beAvoided) or 2 (Solvents to Be Limited).

In addition, methyl nicotinate is included in the U.S. FDA's EAFUS list,which contains ingredients added directly to food that the FDA haseither approved as food additives, or has listed or affirmed as beingGRAS.

Depending on the manner in which the crystalline form of the presentinvention is prepared, and the methodology and instrument used for PXRDanalysis, the intensity of a given peak observed in a PXRD diffractogramof the crystalline form may vary when compared to the same peak in therepresentative PXRD diffractogram provided in FIG. 1. Thus, differencesin relative peak intensities between peaks in a PXRD diffractogram for agiven crystalline form may be observed when compared to the relativepeak intensities of the peaks in the representative PXRD diffractogramof FIG. 1. Any such differences may be due, in part, to the preferredorientation of the sample and its deviation from the ideal random sampleorientation, the preparation of the sample for analysis, and themethodology applied for the analysis. Such variations are known andunderstood by a person of skill in the art, and any such variations donot depart from the invention disclosed herein.

In addition to the differences in relative peak intensities that may beobserved in comparison to the representative PXRD diffractogram providedin FIG. 1, it is understood that individual peak positions may varybetween ±0.2° 2θ from the values observed in the representative PXRDdiffractograms provided in FIG. 1 for the crystalline forms of theinvention, or listed in Table 1. Such variations are known andunderstood by a person of skill in the art, and any such variations donot depart from the invention disclosed herein.

Further, it is understood that, depending on the instrument used forX-ray analysis and its calibration, uniform offsets in the peak positionof each peak in a PXRD diffractogram of greater that 0.2° 2θ may beobserved when compared to the representative PXRD diffractogramsprovided in FIG. 1. Thus, PXRD diffractograms of the crystalline formsof the present invention may, in some circumstances, display the samerelative peak positions as observed in the representative PXRDdiffractograms provided in FIG. 1, with the exception that each peak isoffset in the same direction, and by approximately the same amount, suchthat the overall PXRD diffractogram is substantially the same inappearance as the PXRD diffractogram of FIG. 1, with the exception ofthe uniform offset in peak positions. The observation of any suchuniform peak shift in a PXRD diffractogram does not depart from theinvention disclosed herein given that the relative peak positions of theindividual peaks within the PXRD diffractogram remain consistent withthe relative peak positions observed in the PXRD diffractograms of FIG.1 for the crystalline form of the invention.

As used herein, the term ‘crystalline form’ refers to a substance with aparticular arrangement of molecular components in its crystal lattice,and which may be identified by physical characterization methods such asPXRD. As used herein, the term crystalline form is intended to refer toboth single-component and multiple-component forms. Single componentforms of Eluxadoline, such as those known in the art, consist solely ofEluxadoline, in the repeating unit of the crystalline lattice ofEluxadoline. Multiple component forms of Eluxadoline, such as theco-crystal of the present invention, include crystalline forms ofEluxadoline wherein one or more molecules are also incorporated into thecrystal lattice with Eluxadoline.

As used herein, the term ‘co-crystal’ refers to a multiple-componentcrystalline form containing both Eluxadoline and a co-former, methylnicotinate, that is solid under ambient conditions.

Multi-component crystalline forms comprising more than one type ofmolecule, such as co-crystals, may have some variability in the exactmolar ratio of their components depending on a variety of factors. Forexample, a molar ratio of components within a multi-componentcrystalline form provides a person of skill in the art information as tothe general relative quantities of the components of the crystallineform. In many cases, the molar ratio may vary by ±20% from a statedrange. For example, with respect to the present invention, a molar ratioof 1:1 should be understood to include the ratios 1:0.8 and 1:1.2, aswell as all of the individual ratios in between.

As used herein, the term “room temperature” refers to a temperature inthe range of 20° C. to 25° C.

Unless defined otherwise herein, the term “approximately”, when used inreference to molar ratios, allows for a variance of plus or minus 10%.

When describing the embodiments of the present invention there may be acommon variance to a given temperature or time that would be understoodor expected by the person skilled in the art to provide substantiallythe same result. For example, when reference is made to a particulartemperature, it is to be understood by the person skilled in the artthat there is an allowable variance of ±5° C. associated with thattemperature. When reference is made to a particular time, it is to beunderstood that there is an allowable variance of ±10 minutes when thetime is one or two hours, and ±1 hour when longer periods of time arereferenced.

In one embodiment of the present invention, there is provided a newcrystalline form of Eluxadoline, Eluxadoline Form APO-I, which is aco-crystal of Eluxadoline and methyl nicotinate. Preferably, inEluxadoline Form APO-I, the molar ratio of Eluxadoline to methylnicotinate is approximately 1:1.

Eluxadoline Form APO-I can be characterized by a PXRD diffractogramcomprising, among other peaks, characteristic peaks, expressed indegrees 2θ (±0.2°), at 6.4°, 6.9° and 11.4°. Preferably, the PXRDdiffractogram further comprises at least three peaks, expressed indegrees 2θ (±0.2°), selected from the group consisting of 8.7°, 9.9°,12.7°, 14.8°, 15.8°, 17.5°, 18.9°, 19.8° and 23.8°. More preferably, thePXRD diffractogram further comprises peaks, expressed in degrees 2θ(±0.2°), at 8.7°, 9.9°, 12.7°, 14.8°, 15.8°, 17.5°, 18.9°, 19.8° and23.8°. PXRD studies of capped and uncapped samples of Eluxadoline FormAPO-I have shown that this crystal form is stable following storage instability chambers maintained at 27° C./60% RH and 40° C./75% RH for atleast 10 days.

An illustrative PXRD diffractogram of Eluxadoline Form APO-I, asprepared in Example 1, is shown in FIG. 1. A peak listing, comprisingrepresentative peaks from the PXRD diffractogram in FIG. 1, and theirrelative intensities, is provided in Table 1. Although illustrative ofthe PXRD diffractogram that is provided for the Eluxadoline Form APO-Iof the present invention, the relative intensities of the peaks arevariable. Thus, depending on a particular sample, the prominence orrelative intensity of the peaks observed may differ from those in theillustrative PXRD diffractogram and peak listing.

TABLE 1 Relative peak intensities of Eluxadoline Form APO-I from FIG. 1Angle (° 2θ) Relative intensity (%) 6.42 73.9 6.86 34.9 8.74 5.7 9.8827.0 11.39 100 12.74 69.8 14.75 43.0 15.83 27.9 17.46 51.3 18.89 52.019.82 57.5 23.78 29.6

As described in Examples 1 to 3, Eluxadoline Form APO-I can be preparedby combining methyl nicotinate and Eluxadoline in a solvent, preferablya C1-C3 alcohol selected from the group consisting of methanol, ethanol,n-propanol and 2-propanol, and most preferably 2-propanol; andmaintaining the mixture at a suitable temperature, preferably betweenapproximately room temperature and approximately 80° C., and morepreferably at approximately 60° C., followed by a brief period ofcooling, if necessary. Preferably, Eluxadoline and methyl nicotinate arecombined in a molar ratio of Eluxadoline:methyl nicotinate of betweenapproximately 1:25 and approximately 1:60, more preferably betweenapproximately 1:35 and approximately 1:55. Filtration of the resultingsuspension provides Eluxadoline Form APO-I having a PXRD diffractogramconsistent with FIG. 1. Preferably, washing of the damp filter cake withpure solvent prior to drying is avoided. Instead, if desired, followingfiltration and drying, the isolated Eluxadoline Form APO-I may becombined with a hydrocarbon solvent, preferably cyclohexane, and allowedto stir for a time under ambient conditions to wash away any impurities,such as excess methyl nicotinate. Further filtration and drying providespurified Eluxadoline Form APO-I, free of excess methyl nicotinate.

In a further embodiment of the invention, there is provided apharmaceutical composition of a co-crystal of Eluxadoline and methylnicotinate with one or more pharmaceutically acceptable excipients.Preferably, the pharmaceutical composition is a solid dosage formsuitable for oral administration, such as a capsule, tablet, pill,powder or granulate. Most preferably, the pharmaceutical composition isa tablet. Preferably, the pharmaceutical composition provides a dose ofEluxadoline that is equivalent to the 75 mg or 100 mg of Eluxadolinefound in VIBERZI® drug products.

Suitable pharmaceutically acceptable excipients are preferably inertwith respect to the crystalline form of Eluxadoline of the presentinvention, and may include, for example, one or more excipients selectedfrom binders such as lactose, starches, modified starches, sugars, gumacacia, gum tragacanth, guar gum, pectin, wax binders, microcrystallinecellulose, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,copolyvidone, gelatine, polyvinylpyrollidone (PVP) and sodium alginate;fillers or diluents such as lactose, sugar, starches, modified starches,mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g.,microcrystalline cellulose, cellulose), calcium sulphate, xylitol andlactitol; disintegrants such as croscarmellose sodium, crospovidone,polyvinylpyrrolidone, sodium starch glycollate, corn starch,microcrystalline cellulose, hydroxypropyl methylcellulose andhydroxypropyl cellulose; lubricants such as magnesium stearate,magnesium lauryl stearate, sodium stearyl fumarate, stearic acid,calcium stearate, zinc stearate, potassium benzoate, sodium benzoate,myristic acid, palmitic acid, mineral oil, hydrogenated castor oil,medium-chain triglycerides, poloxamer, polyethylene glycol and talc; anddispersants or solubility enhancing agents, such cyclodextrins, glycerylmonostearate, hypromellose, meglumine, Poloxamer, polyoxyethylene castoroil derivatives, polyoxyethylene stearates, polyoxylglycerides,povidone, and stearic acid. Other excipients including preservatives,stabilisers, anti-oxidants, silica flow conditioners, antiadherents orglidants may be added as required. Other suitable excipients and thepreparation of solid oral dosage forms is well known to person of skillin the art, and is described generally, for example, in Remington TheScience and Practice of Pharmacy 21^(st) Edition (Lippincott Williams &Wilkins: Philadelphia; 2006; Chapter 45).

Optionally, when the pharmaceutical compositions are solid dosage forms,the solid dosage forms may be prepared with coatings, such as entericcoatings and extended release coatings, using standard pharmaceuticalcoatings. Such coatings, and their application, are well known topersons skilled in the art, and are described, for example, in RemingtonThe Science and Practice of Pharmacy 21^(st) Edition (LippincottWilliams & Wilkins: Philadelphia; 2006; Chapter 46).

EXAMPLES

The following non-limiting examples are illustrative of some of theaspects and embodiments of the invention described herein.

The Eluxadoline used as a starting material in the following exampleswas consistent with Eluxadoline Form a, which is reported in WO2009/009480 A2. However, other polymorphic forms are equally suitable asstarting material, provided that they have some solubility in thesolvent system used such that dissolution of the initial crystallineform and crystallization of the co-crystal of the present inventionoccurs over the course of the preparation.

PXRD Analysis:

PXRD diffractograms were recorded on a Bruker D8 Discover powder X-raydiffractometer (Bruker-AXS, Karlsruhe, Germany). The generator was aMicro-focus X-ray source (IMSTube: Cu tube with 1.54184 A) with avoltage of 50 kV and current of 1.00 mA, using a divergence slit of 0.3mm and collimator of 0.3 mm. For each sample, one frame was collectedusing a still scan with a Pilatus 3R-100 kA detector at the distance of154.72 mm from the sample. Raw data were evaluated using the program EVA(Bruker-AXS, Karlsruhe, Germany).

Example 1: Preparation of Eluxadoline Form APO-I

Eluxadoline (400 mg) was treated with a prepared solution (67 mL) ofmethyl nicotinate (24 g) in isopropanol (72 mL), and the resultingsuspension was stirred at 60° C. for 3 hours. The suspension was thenremoved from the heat source and allowed to cool for approximately 15minutes. The resulting solid was collected by filtration and dried invacuo at room temperature overnight to afford Eluxadoline Form APO-I(457 mg). ¹H NMR analysis of the solid (d₆-DMSO) showed a molar ratio ofEluxadoline:methyl nicotinate of approximately 1:1, as well as a mixtureof rotamers (indicated as minor and major in assignment that followsbelow). The PXRD diffractogram of a sample prepared by this method isshown in FIG. 1.

¹H-NMR (DMSO-d₆, 400 MHz) δ: 9.09 (1H, d, J=1.84 Hz), 8.82 (1H, d,J=4.72 Hz), 8.30 (1H, J=6.36 Hz), 7.95, (2H br s), 7.87-7.15 (11H, m),6.96 (1H, J=8.48 Hz), 6.83-6.77 (1H, m), 5.72 minor, 5.23 major (1H, q,J=6.9 Hz), 4.64-4.38 (m, 3H), 4.00 (1H, d, J=15.4 Hz), 3.89 (s, 3H),3.72 major, 3.69 minor (s, 3H), 3.11-2.67 (6H, m), 2.38 major, 2.05minor (3H, s), 1.43 minor, 1.12 major (d, 3H, J=6.9 Hz) ppm.

Example 2: Preparation of Eluxadoline Form APO-I

Eluxadoline (500 mg) was treated with a prepared solution (15 mL) ofmethyl nicotinate (24 g) in isopropanol (72 mL), and the resultingsuspension was stirred at 60° C. for 4 hours. The suspension was thenremoved from the heat source and allowed to cool for approximately 5minutes. The resulting solid was collected by filtration and dried invacuo at room temperature overnight to afford Eluxadoline Form APO-I(462 mg). The PXRD diffractogram of a sample prepared by this method wasconsistent with the PXRD shown in FIG. 1.

Example 3: Preparation of Eluxadoline Form APO-I

Eluxadoline (450 mg) was treated with a prepared solution (13.5 mL) ofmethyl nicotinate (5 g) in isopropanol (15 mL), and the resultingsuspension was stirred at 60° C. for 3 hours. The suspension was thenremoved from the heat source and the solid immediately collected byfiltration and dried in vacuo at room temperature overnight to affordcrude material (455 mg). To remove any excess methyl nicotinate, thecrude Eluxadoline Form APO-I was suspended in cyclohexane (2.5 mL),stirred for approximately 15 minutes, and the solid was again collectedby filtration, with the residual methyl nicotinate being removed alongwith any other soluble impurities, to afford Eluxadoline Form APO-I (430mg). The PXRD diffractogram of a sample prepared by this method wasconsistent with the PXRD shown in FIG. 1.

What is claimed is:
 1. A crystalline form of Eluxadoline that is aco-crystal of Eluxadoline and methyl nicotinate characterized by a PXRDdiffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at6.4°, 6.9° and 11.4.
 2. The co-crystal of claim 1, wherein the molarratio of Eluxadoline to methyl nicotinate is between approximately 1:0.5and approximately 1:1.5.
 3. The co-crystal of claim 1, wherein the molarratio of Eluxadoline to methyl nicotinate is approximately 1:1.
 4. Theco-crystal of claim 1, further comprising at least three peaks,expressed in degrees 2θ (±0.2°), selected from the group consisting of:8.7°, 9.9°, 12.7°,14.8°, 15.8°, 17.5°, 18.9°, 19.8° and 23.8°.
 5. Theco-crystal of claim 1, further comprising peaks, expressed in degrees 2θ(±0.2°), at 8.7°, 9.9°, 12.7°, 14.8°, 15.8°, 17.5°, 18.9°, 19.8° and23.8°.
 6. The co-crystal of claim 1, providing a PXRD diffractogramsubstantially the same in appearance as the PXRD diffractogram providedin FIG.
 1. 7. The co-crystal of claim 4, wherein the molar ratio ofEluxadoline to methyl nicotinate is approximately 1:1.